Arteriovenous malformations (AVMs) are defects of the circulatory system that are generally believed to arise during embryonic or fetal development or soon after birth. They are comprised of snarled tangles of arteries and veins. The presence of an AVM disrupts the flow of blood through the body. Although AVMs can develop in many different sites, those located in the brain or spinal cord can have especially widespread effects on the body. AVMs of the brain or spinal cord (neurological AVMs) are believed to affect approximately 300,000 Americans. They occur in males and females of all racial or ethnic backgrounds at roughly equal rates.
Most people with neurological AVMs experience few, if any, significant symptoms, and the malformations tend to be discovered only incidentally, usually either at autopsy or during treatment for an unrelated disorder. But for about 12 percent of the affected population (about 36,000 of the estimated 300,000 Americans with AVMs), these abnormalities, also called lesions, cause symptoms that vary greatly in severity. For a small fraction of the individuals within this group, such symptoms are severe enough to become debilitating or even life-threatening. Each year about one percent of those with AVMs will die as a direct result of the lesions, largely due to brain hemorrhages.
Seizures and headaches are the most generalized symptoms of AVMs, but no particular type of seizure or headache pattern has been identified. Seizures can be partial or total, involving a loss of control over movement, convulsions, or a change in a person's level of consciousness. Headaches can vary greatly in frequency, duration, and intensity, sometimes becoming as severe as migraines. Sometimes a headache consistently affecting one side of the head may be closely linked to the site of an AVM. More frequently, however, the location of the pain is not specific to the lesion and may encompass most of the head.
AVMs also can cause a wide range of more specific neurological symptoms that vary from person to person, depending primarily upon the location of the AVM. Such symptoms may include muscle weakness or paralysis in one part of the body; a loss of coordination (ataxia) that can lead to such problems as gait disturbances; apraxia, or difficulties carrying out tasks that require planning; dizziness; visual disturbances such as a loss of part of the visual field; an inability to control eye movement; papilledema (swelling of a part of the optic nerve known as the optic disk); various problems using or understanding language (aphasia); abnormal sensations such as numbness, tingling, or spontaneous pain (paresthesia or dysesthesia); memory deficits; and mental confusion, hallucinations, or dementia. Researchers have recently uncovered evidence that AVMs may also cause subtle learning or behavioral disorders in some people during their childhood or adolescence, long before more obvious symptoms become evident.
One of the more distinctive signs indicating the presence of an AVM is an auditory phenomenon, or bruit: the rhythmic, whooshing sound caused by excessively rapid blood flow through the arteries and veins of an AVM. When audible to patients, bruit may compromise hearing, disturb sleep, or cause significant psychological distress.
Symptoms caused by AVMs can appear at any age, but because these abnormalities tend to result from a slow buildup of neurological damage over time they are most often noticed when people are in their twenties, thirties, or forties. If AVMs do not become symptomatic by the time people reach their late forties or early fifties, the lesions tend to remain stable and rarely produce symptoms. In women, pregnancy sometimes causes a sudden onset or worsening of symptoms, due to accompanying cardiovascular changes, especially increases in blood volume and blood pressure.
In contrast to the vast majority of neurological AVMs, one especially severe type causes symptoms to appear at, or very soon after, birth. Called a vein of Galen defect after the major blood vessel involved, this lesion is located deep inside the brain. It is frequently associated with hydrocephalus (swelling of the brain, often with visible enlargement of the head), swollen veins visible on the scalp, seizures, failure to thrive, and congestive heart failure. Children born with this condition who survive past infancy often remain developmentally impaired.
AVMs become symptomatic only when the damage they cause to the brain or spinal cord reaches a critical level. This is one of the reasons why a relatively small fraction of people with these lesions experiences significant health problems related to the condition. AVMs damage the brain or spinal cord through three basic mechanisms: by reducing the amount of oxygen reaching neurological tissues; by causing bleeding (hemorrhage) into surrounding tissues; and by compressing or displacing parts of the brain or spinal cord.
AVMs compromise oxygen delivery to the brain or spinal cord by altering normal patterns of blood flow. Arteries and veins are normally interconnected by a series of progressively smaller blood vessels that control and slow the rate of blood flow. Oxygen delivery to surrounding tissues takes place through the thin, porous walls of the smallest of these interconnecting vessels, known as capillaries, where the blood flows most slowly. The arteries and veins that make up AVMs, however, lack this intervening capillary network. Instead, arteries dump blood directly into veins through a passageway called a fistula. The flow rate is uncontrolled and extremely rapid, too rapid to allow oxygen to be dispersed to surrounding tissues. When starved of normal amounts of oxygen, the cells that make up these tissues begin to deteriorate, sometimes dying off completely.
This abnormally rapid rate of blood flow frequently causes blood pressure inside the vessels located in the central portion of an AVM directly adjacent to the fistula, the nidus, to rise to dangerously high levels. The arteries feeding blood into the lesion often become swollen and distorted; the veins that drain blood away from it often become abnormally constricted (a condition called stenosis). Moreover, the walls of the involved arteries and veins are often abnormally thin and weak. Aneurysms (balloon-like bulges in blood vessel walls that are susceptible to rupture) may develop in association with approximately half of all neurological AVMs due to this structural weakness.
Bleeding can result from this combination of high internal pressure and vessel wall weakness. Such hemorrhages are often microscopic in size, causing limited damage and few significant symptoms. Even many nonsymptomatic AVMs show evidence of past bleeding. But massive hemorrhages can occur if the physical stresses caused by extremely high blood pressure, rapid blood flow rates, and vessel wall weakness are great enough. If a large enough volume of blood escapes from a ruptured AVM into the surrounding brain, the result can be a catastrophic stroke. AVMs account for approximately two percent of all hemorrhagic strokes that occur each year.
Even in the absence of bleeding or significant oxygen depletion, large AVMs can damage the brain or spinal cord simply by their presence. They can range in size from a fraction of an inch to more than 2.5 inches in diameter, depending on the number and size of the blood vessels making up the lesion. The larger the lesion, the greater the amount of pressure it exerts on surrounding brain or spinal cord structures. The largest lesions may compress several inches of the spinal cord or distort the shape of an entire hemisphere of the brain. Such massive AVMs can constrict the flow of cerebrospinal fluid by distorting or closing the passageways and open chambers, or ventricles, inside the brain that allow this fluid to circulate freely. As cerebrospinal fluid accumulates, neurological tissues begin to swell, and in extreme cases, hydrocephalus results. This fluid buildup further increases the amount of pressure on fragile neurological structures, adding to the damage caused by the AVM itself.
AVMs can form virtually anywhere in the brain or spinal cord, wherever arteries and veins exist. Some are formed from blood vessels located in the dura mater or in the pia mater, the outermost and innermost, respectively, of the three membranes surrounding the brain and spinal cord. (The third membrane, called the arachnoid, lacks blood vessels.)
AVMs affecting the spinal cord are of two types, AVMs of the dura mater, which affect the function of the spinal cord by transmitting excess pressure to the venous system of the spinal cord; and AVMs of the spinal cord itself, which affect the function of the spinal cord by hemorrhage by reducing blood flow to the spinal cord, or by causing excess venous pressure. Spinal AVMs frequently cause attacks of sudden, severe back pain, often concentrated at the roots of nerve fibers where they exit the vertebrae; the pain is similar to that caused by a slipped disk. These lesions also can cause sensory disturbances, muscle weakness, or paralysis in the parts of the body served by the spinal cord or the damaged nerve fibers. Spinal cord injury by the AVM by either of the mechanisms described above can lead to degeneration of the nerve fibers within the spinal cord below the level of the lesion, causing widespread paralysis in parts of the body controlled by those nerve fibers.
Dural and pial AVMs can appear anywhere on the surface of the brain. Those located on the surface of the cerebral hemispheres exert pressure on the cerebral cortex. Depending on their location, these AVMs may damage portions of the cerebral cortex involved with thinking, speaking, understanding language, hearing, taste, touch, or initiating and controlling voluntary movements. AVMs located on the frontal lobe close to the optic nerve or on the occipital lobe, the rear portion of the cerebrum where images are processed, may cause a variety of visual disturbances.
AVMs also can form from blood vessels located deep inside the interior of the cerebrum. These AVMs may compromise the functions of three vital structures: the thalamus, which transmits nerve signals between the spinal cord and upper regions of the brain; the basal ganglia surrounding the thalamus, which coordinate complex movements; and the hippocampus, which plays a major role in memory.
AVMs can affect other parts of the brain besides the cerebrum. The hindbrain is formed from two major structures: the cerebellum, which is nestled under the rear portion of the cerebrum, and the brainstem, which serves as the bridge linking the upper portions of the brain with the spinal cord. These structures control finely coordinated movements, maintain balance, and regulate some functions of internal organs, including those of the heart and lungs. AVM damage to these parts of the hindbrain can result in dizziness, giddiness, vomiting, a loss of the ability to coordinate complex movements such as walking, uncontrollable muscle tremors, or disruptions in organ function (for example, heart failure).
The greatest potential danger posed by AVMs is hemorrhage. Researchers believe that each year between two and four percent of all AVMs hemorrhage. Most episodes of bleeding remain undetected at the time they occur because they are not severe enough to cause significant neurological damage. But massive, even fatal, bleeding episodes do occur. The present state of knowledge does not permit doctors to predict whether or not any particular person with an AVM will suffer an extensive hemorrhage. The lesions can remain stable or can suddenly begin to grow. In a few cases, they have been observed to regress spontaneously.
Besides AVMs, three other main types of vascular lesion can arise in the brain or spinal cord: cavernous malformations, capillary telangiectases, and venous malformations. These lesions may form virtually anywhere within the central nervous system, but unlike AVMs, they are not caused by high-velocity blood flow from arteries into veins. In contrast, cavernous malformations, telangiectases, and venous malformations are all low-flow lesions. Instead of a combination of arteries and veins, each one involves only one type of blood vessel. These lesions are less unstable than AVMs and do not pose the same relatively high risk of significant hemorrhage. In general, low-flow lesions tend to cause fewer troubling neurological symptoms and require less aggressive treatment than do AVMs.
Cavernous malformations are lesions formed from groups of tightly packed, abnormally thin-walled, small blood vessels that displace normal neurological tissue in the brain or spinal cord. The vessels are filled with slow-moving or stagnant blood that is usually clotted or in a state of decomposition. Like AVMs, cavernous malformations can range in size from a few fractions of an inch to several inches in diameter, depending on the number of blood vessels involved. Some people develop multiple lesions. Although cavernous malformations usually do not hemorrhage as severely as AVMs do, they sometimes leak blood into surrounding neurological tissues because the walls of the involved blood vessels are extremely fragile. Although they are often not as symptomatic as AVMs, cavernous malformations can cause seizures in some people. After AVMs, cavernous malformations are the type of vascular lesion most likely to require treatment.
Capillary telangiectases are lesions that consist of groups of abnormally swollen capillaries and usually measure less than an inch in diameter. Capillaries are the smallest of all blood vessels, with diameters smaller than that of a human hair; they have the capacity to transport only small quantities of blood, and blood flows through these vessels very slowly. Because of these factors, telangiectases rarely cause extensive damage to surrounding brain or spinal cord tissues. Any isolated hemorrhages that occur are microscopic in size. Thus, the lesions are usually benign. However, in some inherited disorders in which people develop large numbers of these lesions, telangiectases can contribute to the development of nonspecific neurological symptoms such as headaches or seizures.
Finally, venous malformations are lesions that consist of abnormally enlarged veins. The structural defect usually does not interfere with the function of the blood vessels, which is to drain oxygen-depleted blood away from the body's tissues and return it to the lungs and heart. Venous malformations rarely hemorrhage. As with telangiectases, most venous malformations do not produce symptoms, remain undetected, and follow a benign course.
Physicians now use an array of traditional and new imaging technologies to uncover the presence of AVMs. Angiography provides the most accurate pictures of blood vessel structure in AVMs. The technique requires injecting a special water-soluble dye, called a contrast agent, into an artery. The dye highlights the structure of blood vessels so that it can be recorded on conventional X-rays. Although angiography can record fine details of vascular lesions, the procedure is somewhat invasive and carries a slight risk of causing a stroke.
Two of the most frequently employed noninvasive imaging technologies used to detect AVMs are computed axial tomography (CT) and magnetic resonance imaging (MRI) scans. CT scans use X-rays to create a series of cross-sectional images of the head, brain, or spinal cord and are especially useful in revealing the presence of hemorrhage. MRI imaging, however, offers superior diagnostic information by using magnetic fields to detect subtle changes in neurological tissues. A recently developed application of MRI technology (magnetic resonance angiography or MRA) can record the pattern and velocity of blood flow through vascular lesions as well as the flow of cerebrospinal fluid throughout the brain and spinal cord. Both MRI and MRA can provide three-dimensional representations of AVMs by taking images from multiple angles.
Medication can often alleviate general symptoms such as headache, back pain, and seizures caused by AVMs and other vascular lesions. However, the definitive conventional treatment for AVMs is surgery.
The decision to perform surgery on any individual with an AVM requires a careful consideration of possible benefits versus risks. The natural history of an individual AVM is difficult to predict; however, left untreated, they have the potential of causing significant hemorrhage, which may result in serious neurological deficits or death. On the other hand, surgery on any part of the central nervous system carries its own risks as well; AVM surgery is associated with an estimated eight percent risk of serious complications or death. There is no easy formula that can allow physicians and their patients to reach a decision on the best course of therapyCCall therapeutic decisions must be made on a case-by-case basis.
Today, three surgical options exist for the treatment of AVMs: conventional surgery, radiosurgery, and endovascular embolization.
Conventional surgery involves entering the brain or spinal cord and removing the central portion of the AVM, including the fistula, while causing as little damage as possible to surrounding neurological structures. One description of this type of surgical treatment is described in Hillman and Pare, the disclosures of which are incorporated herein by reference. (Hillman, J.; “Population based analysis of arteriovenous malformation treatment” J. Neurosurg., 2001 October; 95(4):633 637; and Pare, M. C., Bojanowski, M., “Surgical Treatment of AVMs in Eloquent Zones of the Brain: Apropos of Eleven Cases”, Ann. Chir., 1991; 45(9): 811 5.) This surgery is most appropriate when an AVM is located in a superficial portion of the brain or spinal cord and is relatively small in size. However, AVMs located deep inside the brain generally cannot be approached through conventional surgical techniques because there is too great a possibility that functionally important brain tissue will be damaged or destroyed.
Endovascular embolization and radiosurgery are less invasive than conventional surgery and offer safer treatment options for AVMs located deep inside the brain. Radiosurgery is the least invasive therapeutic approach. It involves aiming a beam of highly focused radiation directly on the AVM. The high dose of radiation damages the walls of the blood vessels making up the lesion. Radiosurgical techniques have been described by Wallace and Irie, the disclosures of which are incorporated herein by reference. (Wallace, R., Bourekas, E., “Brain Arteriovenous Malformations”, Neuroimaging Clin. N. America, 1998 May; 8(2): 383 99; and Irie, K., Nagao, S., Honma, Y., Kunishio, K., Ogawa, T., Kawai, N. “Treatment of arteriovenous malformation of the brain preliminary experience”, J. Clin. Neurosci., 2000 September; 7 Supple 1:24 29.) Over the course of the next several months, the irradiated vessels gradually degenerate and eventually close, leading to the resolution of the AVM.
Although radiosurgery is minimally invasive, it is not as effective as conventional surgery. Radiosurgery often has incomplete results, particularly when an AVM is large, and it poses the additional risk of radiation damage to surrounding normal tissues. Moreover, even when successful, complete obliteration of an AVM takes place over the course of many months following radiosurgery. During that period, the risk of hemorrhage is still present, and may in fact be higher.
The most promising technique is endovascular embolization. In this technique the surgeon guides a catheter though the arterial network until the tip reaches the site of the AVM. The surgeon then introduces a substance that will plug the malformation, correcting the abnormal pattern of blood flow. This process is known as embolization because it causes an embolus (a material which can obstruct or occlude blood flow) to travel through blood vessels, eventually becoming lodged in a vessel and obstructing blood flow. Embolization techniques are discussed generally by Jizong, Liu, Vernon, and Wallace the disclosures of which are incorporated herein by reference. (Jizong, Z., Shou, W., Jingsheng, L., Dali, S., Yuanli, Z., Yan, Z., “Combination of intraoperative embolisation with surgical resection for treatment of giant cerebral arteriovenous malformations”, J. Clin. Neurosci., 2000 September; 7 Suppl. 1:54 59; Liu, H. M., Huang, Y. C., Wang, Y. H., “Embolization of cerebral arteriovenous malformations with n butyl 2 cyanoacrylate”, J. Formos. Med. Addoc., 2000 December; 99(12):906 913; Vernon, B., et al., “Water Borne, in situ Cross Linked Biomaterials from Phase Segregated Precursors”, Submitted Article to Journal of Biomedical Materials Research. February 2002; and Wallace, R., et al., “The Safety and Effectiveness of Brain AVM Embolization using Acrylic and Particles: The Experience of a Single Institution”, Neurosurgery, 1995 October; 37(4); 606 18.)
The materials used to create an obstruction, occlusion or embolus in the center of an AVM include fast-drying biologically inert glues, fibered titanium coils, and tiny balloons. However, conventional embolization frequently proves incomplete or temporary because the materials being used degrade over time. Since embolization usually does not permanently obliterate the AVM, it is usually used only as an adjunct to surgery to reduce the blood flow through the AVM and make the surgery safer. Moreover, conventional AVM embolization materials (e.g. cyanoacrylates), stick to vessels. For example, cyanoacrylates used in known embolization materials have been known to glue catheters to vessels. These materials are also known to cause vessel cell wall damage or stress in AVM vasculature increasing the chance of incomplete occlusion, vessel rupture or hemorrhage.
To avoid this adhesion, other systems have also been investigated. Preformed polymers dissolved in water miscible organic solvents, such as Dimethyl Sulfoxide (DMSO), have been used for this application clinically. With these materials the polymer precipitates after injection into the vasculature as the solvent is replaced by water. Improvements have been made by replacing the DMSO with less toxic solvents such as N-methyl pyrrolidone (NMP). A further improvement would be the complete elimination of organic solvents with aqueous systems.
Recently, the advantages of waterborne, self-reactive systems have been recognized for this application. In fact two in situ gelling systems have been investigated recently. These are calcium alginate and thermally responsive polymers based on N-isopropylacrylamide. The calcium alginate systems developed by Becker et. al., the disclosure of which is incorporated herein by reference, proved to be biocompatible and mechanically stable; however, this procedure requires the simultaneous injection of two components delivered from two catheters position in separate locations in the vasculature: proximal and distal to the AVM or by double lumen catheters, restricting the viscosity (and thus gel strength) that can be delivered or increasing the catheter diameter and reducing the vessel accessibility. (Becker, T. et al., “Calcium Algenate Gel: A biocompatible and mechanically stable polymer for endovascular treatment”, Journal of Biomedical Materials Research., Vol. 54 (2001), pp. 76 86.)
Accordingly, a need exists for improved embolization materials that would allow safer and more permanent minimally invasive relief of AVMs.